The objectives of this research are to understand and interrelate brain acid-base regulation, brain metabolism, and the control of breathing in the newborn and adult. The research plan is largely based on a hypothesis, developed in the past year, which indicates CSF bicarbonate regulation is determined by two components a) a process at the blood brain barrier sensitive to the level of blood bicarbonate and b) a process within brain tissue sensitive to PCO2. Using the techniques of artificial ventilation with different inspired gas mixtures to control PCO2 and peritoneal dialysis to control the blood bicarbonate level, mechanisms at the blood brain barrier will be examined (e.g. the role of bulk flow and/or diffusion) as will mechanisms in brain tissue (e.g. the relationship of PCO2 sensitive aspects of brain energy and amino acid metabolism to brain acid-base regulation). The effectiveness of these two components of brain acid base regulation will be evaluated in newborn and animal in the situations of normal and high PCO2 and bolld bicarbonate, in adult animals with the combined stress of hypoxia and hypercapnia, and in a natural situation with repeated episodes of asphyxia, the diving seal. The role of different brain cell types (neurons, glia and choroid plexus) in the tissue component of brain acid-base regulation will be examined using four complementary approaches in vitro. To relate brain acid-base regulation and metabolism to the control of breathing, the potassium depleted rat will be used as a model. These animals have altered CSF and brain tissue bicarbonate levels, altered tissue K levels and an abnormal breathing pattern that most probably represents a central abnormality. Brain amino acid and catecholamine metabolism will be evaluated in these animals and in normal animals and the results related to the control of breathing. Similarly, the control of breathing will be examined in the situations in which brain acid base regulation and metabolism are evaluated.